Previous work from this laboratory indicates that 3-methoxy-4- hydroxy- phenylglycol (MHPG) is the principal metabolite of brain norepinephrine (NE) and that a significant fraction of urinary MHPG is derived from the metabolism of NE in brain whereas the bulk of urinary 3-methoxy-4-hydroxy-vanillymandelic acid (VMA) and normetanephrine (NM) is derived from the metabolism of NE in peripheral pools. It has also been found by our group that some depressed patients excrete less than normal quantities of MHPG and that these "low excretors" respond best to treatment with the tricyclic antidepressant imepramine. As an extension of this work, to establish criteria by which "low" and "high" MHPG excretors may be identified, patients have been categorized by a number of different diagnostic schemes, and the relationship of these diagnostic groupings to the excretion of catecholamine metabolites is being examined. Longitudinal studies of cycling patients are also being carried out to determine the relationship between changes in the excretion of urinary catecholamine metabolites and shifts in the patient's affective state. We also plan to continue studies which are already underway to determine what role, if any, state variables such as exercise and anxiety may have in determining the quantities of MHPG and other catecholamine metabolites which are excreted into urine. We plan to continue to pursue the development of new methodologies by which more definitive in vivo measures of the metabolism of brain NE may be obtained. Finally, studies of the routes of formation of MHPG in brain, subcellular localization of enzymes, cofactor requirements, etc., are being carried out.